Neurokinin-1 receptor
Fosaprepitant (MK-0517, L-758,298) is a phosphoryl prodrug for aprepitant. A corticosteroid and a 5-HT 3 receptor antagonist are approved as combination therapies with the selective substance P (NK-1 receptor) antagonist aprepitant to prevent acute and delayed chemotherapy-induced nausea and vomiting. [1]
Neurokinin-1 (NK-1) receptor antagonist . [1]

Fosaprepitant (MK-0517, L-758,298) is a phosphoryl prodrug for aprepitant. A corticosteroid and a 5-HT 3 receptor antagonist are approved as combination therapies with the selective substance P (NK-1 receptor) antagonist aprepitant to prevent acute and delayed chemotherapy-induced nausea and vomiting. [1]

Fosaprepitant is intravenously administered and within 30 minutes, transforms into an aprepitant due to the action of ubiquitous phosphatases. Fosaprepitant has a well-tolerated maximum dosage of 150 mg (1 mg/ml), and its AUC for Fosaprepitant 115 mg and Aprecipitant 125 mg are bioequivalent. On day 1 of a 3-day oral aprepitant regimen, fosaprepitant 115 mg has been submitted for FDA approval as an alternative. On days 2 and 3, oral aprepitant is administered. [1]

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In a ferret animal model, fosaprepitant (the water-soluble phosphoryl prodrug of aprepitant) inhibited acute and delayed cisplatin-induced emesis. A single dose prior to cisplatin decreased emesis over a 72-hour period, and daily dosing eliminated emesis throughout the entire 72-hour observation period. Its anti-emetic activity appeared enhanced when combined with dexamethasone or the 5-HT3 receptor antagonist ondansetron. [1]
In a clinical study of chemotherapy-naïve patients receiving cisplatin, a single intravenous dose of fosaprepitant showed similar control of acute emesis compared to ondansetron but was markedly superior in controlling delayed emesis (72% vs 30% complete control). [1]
In another clinical study, adding intravenous fosaprepitant on day 1 (followed by oral aprepitant or placebo on days 2-5) to dexamethasone improved control of delayed emesis (63-68% without emesis) compared to ondansetron plus dexamethasone (41% without emesis), but was less effective for acute emesis control. [1]

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In a ferret animal model, fosaprepitant (the water-soluble phosphoryl prodrug of aprepitant) inhibited acute and delayed cisplatin-induced emesis. A single dose prior to cisplatin decreased emesis over a 72-hour period, and daily dosing eliminated emesis throughout the entire 72-hour observation period. Its anti-emetic activity appeared enhanced when combined with dexamethasone or the 5-HT3 receptor antagonist ondansetron. [1]
In a clinical study of chemotherapy-naïve patients receiving cisplatin, a single intravenous dose of fosaprepitant showed similar control of acute emesis compared to ondansetron but was markedly superior in controlling delayed emesis (72% vs 30% complete control). [1]
In another clinical study, adding intravenous fosaprepitant on day 1 (followed by oral aprepitant or placebo on days 2-5) to dexamethasone improved control of delayed emesis (63-68% without emesis) compared to ondansetron plus dexamethasone (41% without emesis), but was less effective for acute emesis control. [1]

Sprague-Dawley rats were injected with morphine (10 mg/kg twice daily) and/or fosaprepitant (30 mg/kg once daily) for 7 days. Pain threshold was assessed by the hot plate test. Expression of SP and calcitonin gene-related peptide (CGRP) in the spinal cords of these rats was evaluated by immunohistochemistry.[2]

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Fosaprepitant (also known as MK-0517 and L-758,298) is a water-soluble phosphoryl prodrug for aprepitant, which, when administered intravenously, is converted to aprepitant within 30 min of intravenous administration via the action of ubiquitous phosphatases. Owing to the rapid conversion of fosaprepitant to the active form (aprepitant), fosaprepitant 115 mg provided the same aprepitant exposure in terms of AUC as aprepitant 12 mg orally, and fosaprepitant is expected to provide a correspondingly similar antiemetic effect as aprepitant. Clinical studies have suggested that fosaprepitant could be appropriate as an intravenous alternative to the aprepitant oral capsule. In a study in healthy subjects, fosaprepitant 115 mg was generally well tolerated at a final drug concentration of 1 mg/ml, and fosaprepitant 115 mg was AUC bioequivalent to aprepitant 125 mg. Fosaprepitant in the dose of 115 mg has been approved by the US FDA, the EU and the Australian authorities on day 1 of a 3-day oral aprepitant regimen, with oral aprepitant administered on days 2 and 3. Fosaprepitant may be a useful parenteral alternative to oral aprepitant. Further study is needed to clarify the utility of fosaprepitant in the prevention of CINV and to clarify optimal dosing regimens that may be appropriate substitutes for oral aprepitant[2].

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In a ferret model of cisplatin-induced emesis, fosaprepitant was administered. The protocol involved giving a single dose prior to cisplatin or daily dosing, and emesis was monitored over a 72-hour observation period. The study evaluated its effect alone and in combination with other anti-emetics like dexamethasone or ondansetron. [1]

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In a ferret model of cisplatin-induced emesis, fosaprepitant was administered. The protocol involved giving a single dose prior to cisplatin or daily dosing, and emesis was monitored over a 72-hour observation period. The study evaluated its effect alone and in combination with other anti-emetics like dexamethasone or ondansetron. [1]

Fosapitan diglucamine is a water-soluble phosphoryl prodrug of aprepitant. After intravenous injection, it is rapidly converted into the active drug aprepitant within 30 minutes by phosphatases. [1] The pharmacokinetics of aprepitant (and its converted form, fosapitant) are nonlinear. The time to reach maximum plasma concentration (Tmax) is approximately 4 hours. [1] Aprepitant is primarily metabolized in the liver by the cytochrome P450 enzyme CYP3A4, with minor amounts metabolized by CYP1A2 and CYP2C19. [1] The plasma half-life of aprepitant is 9 to 13 hours, and it is mainly excreted as metabolites. Radioactive material was recovered in urine (57%) and feces (45%) after administration of labeled fosapitant. [1] Aprepitant is a moderate inhibitor and inducer of CYP3A4 and also an inducer of CYP2C9. Concomitant use with drugs metabolized by CYP3A4 (e.g., dexamethasone, methylprednisolone, midazolam) may increase plasma concentrations. Concomitant use with CYP2C9 substrates (e.g., warfarin) may decrease plasma concentrations. [1]
CYP3A4 inhibitors may increase plasma concentrations of aprepitant, while CYP3A4 inducers may decrease plasma concentrations. [1]
In a study of healthy subjects, 115 mg of intravenously administered fosapirate was bioequivalent to 125 mg of orally administered aprepitant in terms of AUC (area under the curve). [1]

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Fosapirate diglucamine is a water-soluble phosphoryl prodrug of aprepitant. After intravenous injection, it is rapidly converted to the active drug aprepitant within 30 minutes by phosphatases. [1]
The pharmacokinetics of aprepitant (and its conversion, fosaprepitant) are nonlinear. The time to reach maximum plasma concentration (Tmax) is approximately 4 hours. [1]
Aprepitant is primarily metabolized in the liver by the cytochrome P450 enzyme CYP3A4, with minor amounts metabolized by CYP1A2 and CYP2C19. [1]
The plasma half-life of aprepitant is 9 to 13 hours, and it is primarily eliminated as metabolites. Radioactive material was detected in urine (57%) and feces (45%) after administration of labeled fosaprepitant. [1]
Aprepitant is a moderate inhibitor and inducer of CYP3A4 and also an inducer of CYP2C9. Its plasma concentration can be increased when used in combination with drugs metabolized by CYP3A4 (e.g., dexamethasone, methylprednisolone, midazolam). Concomitant use with CYP2C9 substrates (e.g., warfarin) may decrease its plasma concentration. [1]
CYP3A4 inhibitors may increase the plasma concentration of aprepitant, while CYP3A4 inducers may decrease its plasma concentration. [1]
In a study of healthy subjects, 115 mg of intravenous fosaprepitant was bioequivalent to 125 mg of oral aprepitant in terms of AUC (area under the curve). [1]

In clinical trials, the most common adverse events (incidence >10%) associated with the aprepitant regimen (fosapite can be converted to aprepitant) included asthenia/fatigue, anorexia, constipation, diarrhea, nausea, and hiccups. [1]
Venous irritation was observed after intravenous infusion of fosapite, and its severity was related to the total dose, concentration, and infusion rate. At a concentration of 1 mg/mL, infusion over 15–30 minutes was well tolerated. Higher concentrations (25 mg/mL) and rapid infusions (over 30 seconds) were associated with venous irritation. [1]
In a bioequivalence study, fosapite at doses of 100–150 mg (1 mg/mL) was well tolerated with no serious adverse events reported. The most common adverse events were mild to moderate headache and infusion site symptoms. [1]
Aprepitant may reduce the effectiveness of oral contraceptives; alternative methods of contraception are recommended. [1]
No clinically significant pharmacokinetic differences were found in patients with mild to moderate hepatic or renal impairment, therefore no dose adjustment was required in these populations. [1]
In clinical trials, the most common adverse events (incidence >10%) associated with the aprepitant regimen (fosapite is convertible to aprepitant) included asthenia/fatigue, anorexia, constipation, diarrhea, nausea, and hiccups. [1]
Venous irritation was observed after intravenous infusion of fosapite and was found to be related to total dose, concentration, and infusion rate. At a concentration of 1 mg/mL and an infusion time of 15–30 minutes, it was well tolerated. Higher concentrations (25 mg/mL) and rapid infusions (within 30 seconds) were associated with venous irritation. [1]
In a bioequivalence study, fosapite at doses of 100–150 mg (1 mg/mL) was well tolerated, and no serious adverse events were reported. The most common adverse events were mild to moderate headache and infusion site symptoms. [1]
Aprepitant may reduce the effectiveness of oral contraceptives; alternative methods of contraception are recommended. [1]
No clinically significant pharmacokinetic differences were observed in patients with mild to moderate hepatic or renal impairment, therefore no dose adjustment is required in these patients. [1]

[1]. Expert Opin Investig Drugs. 2007 Dec;16(12):1977-85.

[2]. Role of fosaprepitant, a neurokinin Type 1 receptor antagonist, in morphine-induced antinociception in rats. Indian J Pharmacol. 2016 Jul-Aug; 48(4): 394-398.
[3]. Fosaprepitant: a neurokinin-1 receptor antagonist for the prevention of chemotherapy-induced nausea and vomiting. Expert Rev Anticancer Ther . 2008 Nov;8(11):1733-42.

Fosaprepitant dimethylglucamine is the dimethylglucamine salt form of Fosaprepitant, a water-soluble N-phosphorylated prodrug of aprepitan with antiemetic activity. After intravenous injection, the drug is rapidly converted to aprepitan and selectively binds to human substance P/neurokine 1 (NK1) receptors in the central nervous system (CNS). This inhibits the binding of endogenous substance P to the receptor, thereby preventing substance P-induced vomiting.

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Fosaprepitant dimethylglucamine is a prodrug of aprepitan that was developed as an alternative to oral aprepitan capsules for the prevention of chemotherapy-induced nausea and vomiting (CINV). [1]
It is usually used in combination with 5-HT3 receptor antagonists and corticosteroids (such as dexamethasone) as part of a combined antiemetic regimen. [1] The proposed mechanism of action involves antagonizing the central nervous system (e.g., brainstem nuclei such as the nucleus of the solitary tract) and possibly substance P on neurokinin-1 (NK-1) receptors in the peripheral nervous system, thereby blocking key pathways involved in the vomiting reflex, particularly effective for delayed chemotherapy-induced nausea and vomiting (CINV). [1] Clinical studies have shown that the addition of aprepitant/fosaprepitant to regimens containing 5-HT3 receptor antagonists and dexamethasone significantly improves control of acute and delayed CINV following highly emetogenic chemotherapy (e.g., high-dose cisplatin). [1] For moderately emetogenic chemotherapy, the addition of aprepitant/fosaprepitant improves the complete response rate within 24 hours and the overall response rate within 120 hours, but does not provide sustained improvement in nausea control. [1] 115 mg of intravenous fosaprepitant has been submitted to the FDA for approval as an alternative to the oral 125 mg aprepitant on the first day of a 3-day antiemetic regimen. [1] Fosaprepitant dimeglumine is a prodrug of aprepitant, developed to replace oral aprepitant capsules for the prevention of chemotherapy-induced nausea and vomiting (CINV). [1] It is usually used in combination with 5-HT3 receptor antagonists and corticosteroids (e.g., dexamethasone) as part of a combined antiemetic regimen. [1] The proposed mechanism of action involves antagonizing substance P on neurokinin-1 (NK-1) receptors in the central nervous system (e.g., brainstem nuclei such as the nucleus of the solitary tract) and possibly in the peripheral nervous system, thereby blocking key pathways involved in the vomiting reflex, particularly effective for delayed phases of chemotherapy-induced nausea and vomiting (CINV). [1] Clinical studies have shown that the addition of aprepitant/fosaprepitant to regimens containing 5-HT3 receptor antagonists and dexamethasone significantly improves control of acute and delayed CINV following highly emetogenic chemotherapy (e.g., high-dose cisplatin). [1] For moderately emetogenic chemotherapy, the addition of aprepitant/fosapidem improved the complete response rate within 24 hours and the overall response rate within 120 hours, but did not provide sustained improvement in nausea control. [1] 115 mg of intravenous fosapidem has been submitted to the FDA for approval as an alternative to oral aprepitant on the first day of a 3-day antiemetic regimen. [1]

C37H56F7N6O16P

1004.8337

1004.34

C, 44.23; H, 5.62; F, 13.23; N, 8.36; O, 25.48; P, 3.08

265121-04-8

Fosaprepitant; 172673-20-0; Fosaprepitant-d4 dimeglumine

136086851

White solid powder

9

21

13

54

1130

7

P(N1C(N([H])C(C([H])([H])N2C([H])([H])C([H])([H])O[C@@]([H])([C@]2([H])C2C([H])=C([H])C(=C([H])C=2[H])F)O[C@]([H])(C([H])([H])[H])C2C([H])=C(C(F)(F)F)C([H])=C(C(F)(F)F)C=2[H])=N1)=O)(=O)(O[H])O[H].O([H])[C@]([H])([C@]([H])(C([H])([H])N([H])C([H])([H])[H])O[H])[C@@]([H])([C@@]([H])(C([H])([H])O[H])O[H])O[H].O([H])[C@]([H])([C@]([H])(C([H])([H])N([H])C([H])([H])[H])O[H])[C@@]([H])([C@@]([H])(C([H])([H])O[H])O[H])O[H]

VRQHBYGYXDWZDL-OOZCZQCLSA-N

InChI=1S/C23H22F7N4O6P.2C7H17NO5/c1-12(14-8-15(22(25,26)27)10-16(9-14)23(28,29)30)40-20-19(13-2-4-17(24)5-3-13)33(6-7-39-20)11-18-31-21(35)34(32-18)41(36,37)38;2*1-8-2-4(10)6(12)7(13)5(11)3-9/h2-5,8-10,12,19-20H,6-7,11H2,1H3,(H,31,32,35)(H2,36,37,38);2*4-13H,2-3H2,1H3/t12-,19+,20-;2*4-,5+,6+,7+/m100/s1

[3-[[(2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)morpholin-4-yl]methyl]-5-oxo-4H-1,2,4-triazol-1-yl]phosphonic acid;(2R,3R,4R,5S)-6-(methylamino)hexane-1,2,3,4,5-pentol

MK0517; MK 0517; MK-0517; Fosaprepitant dimeglumine; Fosaprepitant dimeglumine salt; Ivemend; Fosaprepitant meglumine; MK-0517; Fosaprepitant (dimeglumine); UNII-D35FM8T64X; Emend; Inemend

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: (1). This product is not stable in solution, please use freshly prepared working solution for optimal results.  (2). Please store this product in a sealed and protected environment, avoid exposure to moisture.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

H2O: ~50 mg/mL (~49.8 mM)

Solubility in Formulation 1: 100 mg/mL (99.52 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with sonication.

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 (Please use freshly prepared in vivo formulations for optimal results.)